Menée sur des séquences d'exome de 3 083 paires d'échantillons de tissu tumoral et de tissu sain, cette étude évalue les performances d'une nouvelle méthodologie analytique, MutSigCV, pour résoudre le taux de faux positifs dans l'identification de gènes impliqués dans la cancérogenèse

Mutational heterogeneity in cancer and the search for new cancer-associated genes

Lawrence, Michael S. ; Stojanov, Petar ; Polak, Paz ; Kryukov, Gregory V. ; Cibulskis, Kristian ; Sivachenko, Andrey ; Carter, Scott L. ; Stewart, Chip ; Mermel, Craig H. ; Roberts, Steven A. ; Kiezun, Adam ; Hammerman, Peter S. ; McKenna, Aaron ; Drier, Yotam ; Zou, Lihua ; Ramos, Alex H. ; Pugh, Trevor J. ; Stransky, Nicolas ; Helman, Elena ; Kim, Jaegil ; Sougnez, Carrie ; Ambrogio, Lauren ; Nickerson, Elizabeth ; Shefler, Erica ; Cortes, Maria L. ; Auclair, Daniel ; Saksena, Gordon ; Voet, Douglas ; Noble, Michael ; DiCara, Daniel ; Lin, Pei ; Lichtenstein, Lee ; Heiman, David I. ; Fennell, Timothy ; Imielinski, Marcin ; Hernandez, Bryan ; Hodis, Eran ; Baca, Sylvan ; Dulak, Austin M. ; Lohr, Jens ; Landau, Dan-Avi ; Wu, Catherine J. ; Melendez-Zajgla, Jorge ; Hidalgo-Miranda, Alfredo ; Koren, Amnon ; McCarroll, Steven A. ; Mora, Jaume ; Lee, Ryan S. ; Crompton, Brian ; Onofrio, Robert ; Parkin, Melissa ; Winckler, Wendy ; Ardlie, Kristin ; Gabriel, Stacey B. ; Roberts, Charles W. M. ; Biegel, Jaclyn A. ; Stegmaier, Kimberly ; Bass, Adam J. ; Garraway, Levi A. ; Meyerson, Matthew ; Golub, Todd R. ; Gordenin, Dmitry A. ; Sunyaev, Shamil ; Lander, Eric S. ; Getz, Gad

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively [...]

Menée sur des lignées cellulaires et in vivo, cette étude identifie, au sein d'une région chromosomique fréquemment amplifiée dans divers types de cancer (3q26), deux gènes impliqués dans la cancérogenèse (TOLC1 et SKIL)

Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers

Hagerstrand, Daniel ; Tong, Alexander ; Schumacher, Steven E ; Ilic, Nina ; Shen, Rhine R ; Cheung, Hiu Wing ; Vazquez, Francisca ; Shrestha, Yashaswi ; Kim, So Young ; Giacomelli, Andrew O ; Rosenbluh, Joseph ; Schinzel, Anna C ; Spardy, Nicole A ; Barbie, David A ; Mermel, Craig H ; Weir, Barbara A ; Garraway, Levi A ; Tamayo, Pablo ; Mesirov, Jill P ; Beroukhim, Rameen ; Hahn, William C.

3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage independent growth and a second 3q26 gene, SKIL (SNON), facilitated cell [...]

Cet article passe en revue les travaux récents sur les facteurs et voies de signalisation favorisant l'apparition de translocations génomiques dans les cancers

End-joining, translocations and cancer

Bunting, Samuel F. ; Nussenzweig, André

Fusion genes that are caused by chromosome translocations have been recognized for several decades as drivers of deregulated cell growth in certain types of cancer. In recent years, oncogenic fusion genes have been found in many haematological and solid tumours, demonstrating that translocations are a common cause of malignancy. Sequencing approaches have now confirmed that numerous, non-clonal translocations are a typical feature of cancer cells. These chromosome rearrangements are often [...]

Menée sur 49 patients atteints d'un chondrosarcome, cette étude met notamment en évidence de fréquentes anomalies du gène COL2A1

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

Tarpey, Patrick S. ; Behjati, Sam ; Cooke, Susanna L. ; Van Loo, Peter ; Wedge, David C. ; Pillay, Nischalan ; Marshall, John ; O'Meara, Sarah ; Davies, Helen ; Nik-Zainal, Serena ; Beare, David ; Butler, Adam ; Gamble, John ; Hardy, Claire ; Hinton, Jonathon ; Jia, Ming Ming ; Jayakumar, Alagu ; Jones, David ; Latimer, Calli ; Maddison, Mark ; Martin, Sancha ; McLaren, Stuart ; Menzies, Andrew ; Mudie, Laura ; Raine, Keiran ; Teague, Jon W. ; Tubio, Jose M. C. ; Halai, Dina ; Tirabosco, Roberto ; Amary, Fernanda ; Campbell, Peter J. ; Stratton, Michael R. ; Flanagan, Adrienne M. ; Futreal, P. Andrew

Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We [...]

Menée in vivo, cette étude met en évidence le rôle joué par la voie de signalisation de l'intégrine Bêta 3 dans la leucémie myéloïde aiguë

In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Miller, Peter G ; Al-Shahrour, Fátima ; Hartwell, Kimberly A ; Chu, Lisa P ; Järås, Marcus ; Puram, Rishi V ; Puissant, Alexandre ; Callahan, Kevin P ; Ashton, John ; McConkey, Marie E ; Poveromo, Luke P ; Cowley, Glenn S ; Kharas, Michael G ; Labelle, Myriam ; Shterental, Sebastian ; Fujisaki, Joji ; Silberstein, Lev ; Alexe, Gabriela ; Al-Hajj, Muhammad A ; Shelton, Christopher A ; Armstrong, Scott A ; Root, David E ; Scadden, David T ; Hynes, Richard O ; Mukherjee, Siddhartha ; Stegmaier, Kimberly ; Jordan, Craig T ; Ebert, Benjamin L

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic [...]

Menée à l'aide d'un modèle murin de cancer du pancréas, cette étude met en évidence le rôle joué par la voie de signalisation canonique des protéines Wnt dans la cancérogenèse

Canonical Wnt signaling Is required for pancreatic carcinogenesis

Zhang, Yaqing ; Morris, John P ; Yan, Wei ; Schofield, Heather K ; Gurney, Austin ; Simeone, Diane M ; Millar, Sarah ; Hoey, Timothy ; Hebrok, Matthias ; Pasca di Magliano, Marina

Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process [...]

A partir d'une microdissection de nombreuses cryptes individuelles de 6 adénomes du côlon et d'un polype hyperplasique, cette étude met en évidence le rôle joué par des cellules souches multipotentes et décrit la dynamique d'expansion clonale au cours de l'évolution de la tumeur

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution

Humphries, Adam ; Cereser, Biancastella ; Gay, Laura J. ; Miller, Daniel S. J. ; Das, Bibek ; Gutteridge, Alice ; Elia, George ; Nye, Emma ; Jeffery, Rosemary ; Poulsom, Richard ; Novelli, Marco R. ; Rodriguez-Justo, Manuel ; McDonald, Stuart A. C. ; Wright, Nicholas A. ; Graham, Trevor A.

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones [...]

Menée in vitro, in vivo et sur des échantillons prélevés sur des patients atteints d'un sarcome de Kaposi, cette étude met en évidence des mécanismes par lesquels, en favorisant l'activation de la signalisation NF-κB, la kinase IKKε favorise également une tumorigenèse liée à l'expression d'un récepteur GCPR d'origine virale

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang, Yi ; Lu, Xiaolu ; Zhu, Lining ; Shen, Yan ; Chengedza, Shylet ; Feng, Hao ; Wang, Laiyee ; Jung, Jae U. ; Gutkind, Julio S. ; Feng, Pinghui

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi’s sarcoma. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Ezh2, le facteur de transcription Sox4 favorise une transition épithélio-mésenchymateuse dans les tumeurs mammaires

Sox4 Is a Master Regulator of Epithelial-Mesenchymal Transition by Controlling Ezh2 Expression and Epigenetic Reprogramming

Tiwari, Neha ; Tiwari, Vijay K ; Waldmeier, Lorenz ; Balwierz, Piotr J ; Arnold, Phil ; Pachkov, Mikhail ; Meyer-Schaller, Nathalie ; Schübeler, Dirk ; van Nimwegen, Erik ; Christofori, Gerhard

Gene expression profiling has uncovered the transcription factor Sox4 with upregulated activity during TGF-²-induced epithelial-mesenchymal transition (EMT) in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 [...]

Menée à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la surexpression de la protéine IMP1 dans la croissance tumorale et le processus métastatique d'un cancer colorectal

IMP1 promotes tumor growth, dissemination, and a tumor-initiating cell phenotype in colorectal cancer cell xenografts

Hamilton, Kathryn E. ; Noubissi, Felicite K. ; Katti, Prateek S. ; Hahn, Christopher M. ; Davey, Sonya R. ; Lundsmith, Emma T. ; Klein-Szanto, Andres J. ; Rhim, Andrew D. ; Spiegelman, Vladimir S. ; Rustgi, Anil K.

Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is an mRNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the [...]

Menée à l'aide de modèles murins et sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence le rôle joué par le facteur de transcription ATF3 dans le processus métastatique

Transcription factor ATF3 links host adaptive response to breast cancer metastasis

Wolford, Chris C. ; McConoughey, Stephen J. ; Jalgaonkar, Swati P. ; Leon, Marino ; Merchant, Anand S. ; Dominick, Johnna L. ; Yin, Xin ; Chang, Yiseok ; Zmuda, Erik J. ; x, ; Toole, Sandra A. ; Millar, Ewan K. A. ; Roller, Stephanie L. ; Shapiro, Charles L. ; Ostrowski, Michael C. ; Sutherland, Robert L. ; Hai, Tsonwin

Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur PDEF dans la survie des cellules de cancer du sein ER+

PDEF Promotes Luminal Differentiation and Acts as a Survival Factor for ER-Positive Breast Cancer Cells

Buchwalter, Gilles ; Hickey, Michele M ; Cromer, Anne ; Selfors, Laura M ; Gunawardane, Ruwanthi N ; Frishman, Jason ; Jeselsohn, Rinath ; Lim, Elgene ; Chi, David ; Fu, Xiaoyong ; Schiff, Rachel ; Brown, Myles ; Brugge, Joan S

Breast cancer is a heterogeneous disease and can be classified based on gene expression profiles that reflect distinct epithelial subtypes. We identify prostate-derived ETS factor (PDEF) as a mediator of mammary luminal epithelial lineage-specific gene expression and as a factor required for tumorigenesis in a subset of breast cancers. PDEF levels strongly correlate with estrogen receptor (ER)-positive luminal breast cancer, and PDEF transcription is inversely regulated by ER and GATA3. [...]

Menée à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels une sous-expression de Par-4 favorise la récidive d'un cancer du sein après une chimiothérapie

Par-4 Downregulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy

Alvarez, James V ; Pan, Tien-chi ; Ruth, Jason ; Feng, Yi ; Zhou, Alice ; Pant, Dhruv ; Grimley, Joshua S ; Wandless, Thomas J ; DeMichele, Angela ; Chodosh, Lewis A

Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to [...]

Cet article présente un modèle de cancérogenèse dans lequel une dérégulation épigénétique permet une rapide sélection des cellules tumorales aux dépens de l'hôte

Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host

Timp, Winston ; Feinberg, Andrew P.

Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that [...]

Cet article présente un modèle d'évolution du micro-environnement tumoral dont la première étape nécessite la construction d'une "niche précancéreuse"

The evolution of the cancer niche during multistage carcinogenesis

Barcellos-Hoff, Mary Helen ; Lyden, David ; Wang, Timothy C.

The concept of the tumour microenvironment recognizes that the interplay between cancer cells and stromal cells is a crucial determinant of cancer growth. In this Perspectives article, we propose the novel concept that the tumour microenvironment is built through rate-limiting steps during multistage carcinogenesis. Construction of a 'precancer niche' is a necessary and early step that is required for initiated cells to survive and evolve; subsequent niche expansion and maturation accompany [...]